PROJECT SUMMARY/ABSTRACT HLA class II alleles are the major genetic determinant of rheumatoid arthritis (RA). To date, the majority of studies investigating the role of HLA class II risk in the development of RA have focused on antigen dependent mechanisms. However, emerging evidence suggests that HLA class II alleles may also alter T cell fate and function independent of antigen. The central hypothesis for the proposed studies is that the HLA DRB1*04 and *1001 alleles associated with increased risk of RA promote alterations in T cell fate and function that contribute to the development and progression of RA, independent of antigen specificity. The following four Specific Aims will address this hypothesis. Aim 1 studies will determine the effect of HLA DRB1 RA high risk alleles on the whole transcriptome profiles of CD4 and CD8 T cells in healthy human subjects. Aim 2 studies will determine how HLA DRB1 RA high risk alleles influence the immunophenotype of CD4 and CD8 T cells in healthy human subjects. Aim 3 studies will define the HLA driven exhausted-like T cell phenotype that is enhanced in RA HLA low risk subjects, and explore whether it is due to the HLA DRB1 gene or to other linked genes on the haplotype. Aim 4 studies will determine whether the HLA driven exhaustion-like phenotype is acquired by RA HLA DR4 high risk individuals with RA when treated with abatacept, a therapeutic intervention that blocks T cell activation. Together these studies will advance our understanding of the role of HLA class II alleles in defining T cell signatures and provide insight into disease mechanism. They will also determine whether HLA driven T cell exhaustion is a marker of response to therapy in RA.